Project Abstract/Summary Multiple sclerosis (MS) is a chronic disease that is the leading cause of non-traumatic neurological disability in young adults. The disease is caused by an aberrant immune-mediated attack on the central nervous system, which causes tissue destruction and subsequent neurologic disability. Disease course varies greatly from individual to individual, from relapsing-remitting MS, to primary progressive MS. MS is three times more common in women, but tends to be more severe in men. MS has a significant heritable component, with up to 30% of the disease risk being genetically determined. While recent studies have identified candidate genes that are associated with MS risk, it remains unclear how these genes work and whether these are truly causative. Additionally, it is unclear why some individuals get different forms of this disease, and why there are differences between men and women. These types of questions are very difficult, if not impossible, to address in studies in humans. In this application, we propose to use a mouse model of MS to address this question. Mouse models offer powerful genetic tools, and allow for cause/effect mechanistic studies. We will use a novel mouse genetic model that is designed to better represent the complex genetic structure of human populations, which will allow us to dissect the complex genetic architecture underlying MS pathogenesis, and to identify specific genes responsible for various poorly understood aspects of this disease.